Metabotropic glutamate receptors (mGluRs) are a family of recently cloned glutamate receptors coupled via G-proteins to various second messenger systems or ion channels. Activation of mGluRs has a variety of physiological effects in the hippocampal formation. Eight subtypes of mGluRs have been cloned and can be classified into three major groups. Recent studies have defined many of the physiological roles of the group I mGluRs (mGluR1 and mGluR5) and group III mGluRs (mGluRs4,6,7, and 8) in the hippocampus. However, less is known about the specific roles of the groups II mGluRs (mGluR2 and mGluR3). Preliminary data reveal that a selective agonist of group II mGluRs reduces transmission at the perforant path-dentate gyrus synapse. We hypothesize that group II mGluRs serve as autoreceptors at the lateral and medial perforant path synapses. We propose a series of studies aimed at determining the localization and physiological roles of group II mGluRs in the hippocampal formation. We will produce antibodies for group II mGluRs and use them for immunocytochemical studies to determine synaptic localization of group II mGluRs. We will also test the hypothesis that activation of a receptor with a pharmacological profile consistent with that of group II mGluRs reduces transmission at the perforant path. Finally, we use biophysical techniques to determine the cellular mechanism by which group II mGluR agonists modulate transmission at perforant path synapses.